I. What every physician needs to know.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease characterized by accumulation of triglycerides within the hepatocyte. This ranges from bland steatosis or fat accumulation without inflammation to nonalcoholic steatohepatitis (NASH) which can go on to cause fibrosis and eventually cirrhosis.

NASH is a diagnosis of exclusion. Abdominal imaging is unable to determine which individuals with NAFLD have liver cell death and inflammation (NASH). No specific blood test for NASH is available. Typically a serologic work up for other causes of liver disease should be sent, including antibodies to hepatitis C and hepatitis B surface antigen, anti-nuclear antibody, anti-smooth muscle antibody, ceruloplasmin, alpha-1-anti-trypsin levels, iron indices, anti-mitochondrial antibody, and tissue transglutaminase antibody. A thorough history including alcohol intake, family history and drug use should be taken.

A. History Part I: Pattern Recognition:

NASH usually presents in the fifth and sixth decades of life, although it is becoming increasing prevalent in younger patients. The biggest risk factor for the development of NASH is the metabolic syndrome, comprised of type 2 diabetes mellitus, essential hypertension, elevated fasting triglyceride levels, low high density lipoprotein (HDL) levels, obesity, and in women, polycystic ovarian disease. Patients are usually asymptomatic and present with moderately elevated liver enzymes. Occasionally patients may have non-specific symptoms of vague right upper quadrant pain or fatigue.

B. History Part 2: Prevalence:

The current prevalence of nonalcoholic fatty liver disease is about 10-24% and is on the rise. Men and women are equally affected by the disease. NAFLD prevalence is highest in Hispanics and lowest in African Americans.

C. History Part 3: Competing diagnoses that can mimic Nonalcoholic Steatohepatitis.

A differential diagnosis for NASH is listed below, with distinguishing characteristics alongside.

1. Alcoholic fatty liver disease - History of alcohol abuse defined as more then 1 drink per day in women and two drinks per day in men.

2. Autoimmune hepatitis - Usually have positive anti-nuclear antibody or anti-smooth muscle antibody. May also have history of other autoimmune diseases, especially thyroid disease.

3. Hepatitis B/C - Will have positive serologies. In acute hepatitis B/C, serologies may not yet be positive and a viral load would have to be done to rule out the disease.

5. Medication induced - Careful medication history may reveal the cause such as cytotoxic drugs, metals and other drugs such as amiodarone, estrogens, steroids, hydralazine and highly active antiretroviral therapy (HAART).

6. Hemochromatosis - Elevated iron saturation and ferritin levels.

7. Alpha-1-antitrypsin deficiency - Often have lung disease as a direct result of the alpha-1-antitrypsin deficiency. Will have low serum levels of alpha-1-antrypsin.

8. Wilson's disease: Usually presents younger in life, may have hemolytic anemia, low alkaline phosphatase, Fanconi's syndrome. Usually will have low ceruloplasmin, but ceruloplasmin is an acute phase reactant so may be falsely normal during acute illness. Will have elevated 24 hour urinary copper levels.

D. Physical Examination Findings.

Physical exam is non-specific. Patient's may have an obese abdomen, occasionally have hepatomegaly. If NASH has gone on to become cirrhosis, there may be signs of chronic liver disease on exam.

E. What diagnostic tests should be performed?

Imaging studies may show signs of fatty liver disease, but the gold standard is liver biopsy. Typically, nonalcoholic fatty liver disease refers to steatosis seen on liver biopsy in the absence of significant alcohol consumption that is often associated with the metabolic syndrome, but there are many other secondary causes of steatosis on liver biopsy. Fatty liver disease can be broken down histologically into macrovesicular (large fat droplets) or microvascular (smaller fat droplets) steatosis.

-Surgical procedures such as jejuno-ileal bypass, gastric bypass or significant small bowel resection

-Mushroom poisoning, especially Amanita species which also cause severe zone 3 necrosis in addition to steatosis

These etiologies may be indistinguishable by histology, and therefore, secondary causes of macrovesicular steatosis should be ruled out before assuming the steatosis is related to the metabolic syndrome.

Conventionally, and through this chapter, NAFLD (or NASH if associated with inflammation) refers to metabolic syndrome induced liver disease.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Laboratory studies will show an elevated level of AST and ALT if there is inflammation (NASH), but may be normal if there is steatosis without inflammation. The remainder of the laboratory work-up is aimed at ruling out other causes of liver disease as discussed above.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Abdominal ultrasound is the first line test. Computed tomography (CT) or magnetic resonance imaging (MRI) can enhance liver fat detection but is more expensive. An ultrasound may show a bright liver, CT may show the liver to be less dense than the spleen, and MRI can demonstrate a bright liver on T1 weighted imaging (See Figure 1). Recently, the Food and Drug Administration approved the Fibroscan which is an ultrasound test that measures liver stiffness as a surrogate for fibrosis and can monitor progression of NAFLD.

Figure 1.

MRI liver

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None. A full serologic work up is usually necessary to exclude other liver diseases and often a liver biopsy is necessary to definitively make the diagnosis and to establish degree of fibrosis to guide management and surveillance.

III. Default Management.

The mainstay of management is lifestyle modification including weight loss, a balanced diet, exercise, and control of other metabolic risk factors such as diabetes mellitus, hyperlipidemia, and hypertension. Weight loss should be moderate and gradual. There is emerging data suggesting that gastric bypass with appropriate weight loss is very effective in reversing liver biochemistries as well as steatosis and inflammation on follow up liver biopsies. A balanced diet should include more protein and less fat and easily absorbed carbohydrates (such as fructose). Exercise is an important part of management, and has been shown to improve NASH even in the absence of significant weight loss. Both aerobic sustained exercise and muscle building are beneficial and should both be incorporated.

There is no accepted pharmacologic management specific to fatty liver disease, but medication is often needed for management of diabetes mellitus and other conditions within the metabolic syndrome. There have been mixed data with regards to thiazolidinedione (TZD) use in NASH. The PIVENs Study (Pioglitazone vs Vitamin E vs Placebo for the treatment of 247 Nondiabetic Adults with NASH) which was a randomized controlled clinical trial sponsored by the NIH showed that resolution of histologic NASH occurred more often in patients treated with pioglitazone vs placebo (47 vs 21%, p = 0.001). Unfortunately, many patients on pioglitazone gained weight and liver fibrosis did not improve.

Vitamin E has shown some improvement in steatosis and liver enzymes by reducing oxidant stress, but there have been relatively few studies to date. Metformin may have short term benefit in improving liver enzymes. Atorvastatin has been shown to improve inflammation and has recently been shown to decrease the likelihood of developing fatty liver disease when evaluated by imaging criteria for fatty liver disease.

A. Immediate management.

B. Physical Examination Tips to Guide Management.

Long-term monitoring of the patient's weight to document weight loss is important to ensure the patient is adherent to lifestyle modifications and to give encouragement, as weight loss can be very difficult and requires a strong commitment from the patient and physician. If the patient is not showing signs of weight loss despite adherence to lifestyle modifications, it may be appropriate to discuss bariatric surgery depending on the patient. A Cochrane review concluded that lack of randomized clinical trials prevents definitive benefit or harm of bariatric surgery and in some cases hepatic fibrosis may progress after bariatric surgery. However, given the evidence of improvement of metabolic syndrome with bariatric surgery, use of it is not contraindicated in eligible patients with NAFLD or NASH.

Monitoring liver enzymes provide an idea about the amount of underlying inflammation. It can also provide motivation for the patient if you can document decreasing liver enzymes as the patient continues to lose weight and implement lifestyle changes. If the patient has cirrhosis, monitoring of international normalized ratio (INR), creatinine and bilirubin to calculate MELD (model for end stage liver disease) should be done at regular intervals. If MELD continues to rise or reaches 10-15 points, referral to a liver transplant center should be considered.

D. Long-term management.

Long-term management consists of diet, exercise, weight loss, and controlling metabolic risk factors. Monitoring liver enzymes may be useful in prognostication and determining the need for repeat biopsies. Vaccination for hepatitis A and B will help prevent additional liver damage should the patient be exposed to these viruses.

E. Common Pitfalls and Side-Effects of Management.

It is imperative to rule out other causes of liver disease with serologic work up. Even if liver biopsy is obtained and steatosis with or without inflammation or fibrosis is seen, the secondary causes of fatty liver disease including alcohol, medications, and pregnancy, must be considered. As stated above, no medications have been definitively approved for nonalcoholic steatohepatitis.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

If a patient has underlying liver insufficiency due to another liver disease, nonalcoholic steatohepatitis may make the liver insufficiency worse, and therefore the underlying liver disease should be treated if possible. Additionally, once diagnosed with nonalcoholic steatohepatitis, a patient should be vaccinated against hepatitis A and hepatitis B so as not to exacerbate liver insufficiency.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

Tight glycemic control is very important in the treatment of nonalcoholic steatohepatitis. Otherwise, no change in standard management.

F. Malignancy.

If nonalcoholic steatohepatits leads to cirrhosis, there is an increased risk of hepatocellular carcinoma. Once hepatocellular carcinoma or end stage liver disease develops, the treatment of choice for appropriate patients is liver transplant.

G. Immunosuppression (HIV, chronic steroids, etc).

Steroids may make glycemic control more difficult, which again is important to control when a patient has nonalcoholic steatohepatitis. HAART therapy can cause NASH and should be investigated as a potential cause.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

Many patients with nonalcoholic steatohepatitis are obese but are actually malnourished due to a poor diet. A balanced diet with slow, maintainable weight loss is recommended. Consultation with a dietitian maybe helpful.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

A. Sign-out considerations While Hospitalized.

Unless the patient has developed cirrhosis, NASH does not require any specific sign-out considerations.

B. Anticipated Length of Stay.

NASH does not usually require inpatient care.

C. When is the Patient Ready for Discharge.

If a patient was admitted for evaluation of increased liver enzymes, he/she may be discharged once liver enzymes are relatively stable and other readily reversible causes of liver disease are excluded.

1. When should clinic follow up be arranged and with whom.

If the diagnosis is still in question, follow up with a hepatologist should be considered. If the diagnosis is confirmed, follow up with primary care physician to follow the patient's progress with diet, lifestyle modifications, weight loss, and correlation with liver enzymes maybe sufficient. Follow up with nutritionist for dietary modifications may be useful.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Before clinic follow up, a serologic workup to evaluate for other liver diseases and possibly a liver biopsy to evaluate degree of steatosis, inflammation, and fibrosis should be considered.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Repeat liver enzymes may be helpful to trend after discharge from the hospital.

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

About 5-20% of patients with NASH will go on to develop cirrhosis. Once cirrhosis has developed, the damage is irreversible and can lead to symptoms from portal hypertension and increases the risk of hepatocellular carcinoma. Therefore, diet, exercise, weight loss, risk factor modification are extremely important before its too late.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

None. If the patient has developed cirrhosis, hepatocellular carcinoma and esophageal varices screening are indicated.